Prostate cancer is the most common malignancy and the second leading cause of cancer-related death in American men. Prostate cancer is a biologically and clinically heterogeneous disease. A majority of men with this malignancy harbor slow-growing tumors that may not impact an individual's natural lifespan, while others are struck by rapidly progressive, metastatic tumors. PSA screening is limited by a lack of specificity and an inability to predict which patients are at risk to develop hormone refractory metastatic disease. Recent studies advocating a lower PSA threshold for diagnosis may increase the number of prostate cancer diagnoses and further complicate the identification of patients with indolent vs. aggressive cancers (Punglia et al., N Engl J Med, 349: 335-342 (2003)). New serum and tissue markers that correlate with clinical outcome or identify patients with potentially aggressive disease are urgently needed (Welsh et al., Proc Natl Acad Sci USA, 100: 3410-3415 (2003)).
Recent expression profiling studies suggest that expression signatures for metastatic vs. non-metastatic tumors may reside in the primary tumor (Ramaswamy et al., Nat Genet, 33: 49-54 (2003); Sotiriou et al., Proc Natl Acad Sci USA, 100: 10393-10398 (2003)). Additional features that predispose tumors to metastasize to specific organs may also be present at some frequency in the primary tumor (Kang et al., Cancer Cell, 3: 537-549 (2003)). These recent observations suggest that novel markers of pre-metastatic or pre-hormone refractory prostate cancer may be identified in early stage disease. These markers may also play a role in the biology of metastatic or hormone refractory prostate cancer progression. Recent examples of genes present in primary tumors that correlate with outcome and play a role in the biology of prostate cancer progression include EZH2 and LIM kinase (Varambally et al., Nature, 419: 624-629 (2002); Yoshioka et al., Proc Natl Acad Sci USA, 100: 7247-7252 (2003)). However, neither of these two genes is secreted.
In order to identify new candidate serum or tissue markers of hormone refractory prostate cancer, we compared gene expression profiles of paired hormone dependent and hormone refractory prostate cancer xenografts. The LAPC-9 xenograft was established from an osteoblastic bone metastasis and progresses from androgen dependence to independence following castration in immune deficient mice (Craft et al., Cancer Research, In Press (1999)). It has been used previously to identify candidate therapeutic targets in prostate cancer. Differentially expressed genes were validated and then examined for sequence homology to secreted or cell surface proteins. The identification, characterization and initial validation of N-Cadherin, which is expressed in both hormone refractory prostate cancer and bladder cancer, has been previously reported (WO/2007/109347).
We previously disclosed our identification of N-cadherin as a putative diagnostic and therapeutic target in prostate and bladder cancers (WO/2007/109347). Our previous disclosure demonstrated significant expression of the target in high risk and advanced prostate and bladder tumors and showed that expression of the target is associated with poor prognosis and progression to androgen independence. Although there has been previous speculation that N-cadherin might be a useful therapy target, the only existing drug was a peptide antagonist, which did not show any preclinical activity against prostate cancer. To our knowledge, our invention provides the first monoclonal antibodies that are active against cancers expressing the target. In addition, the exisiting N-cadherin antagonist targets only the first extracellular domain of the protein. We describe antibodies that target the first and fourth extracellular domains. All have significant antitumor activity. To our knowledge, this is the first description of the concept of targeting the fourth extracellular domain. Our antibodies can be used a single agents, in combination, and also conceptually as agents that can be combined with antagonists of parallel or downstream pathways to N-cadherin.
The invention encompasses multiple monoclonal antibodies against the first and fourth extracellular domains of the N-cadherin protein. These antibodies block tumor growth, angiogenesis and metastasis in in vivo models of prostate and other cancers. They work by blocking N-cadherin signal transduction pathways that are critical for tumor growth, invasion, angiogenesis and metastasis. The antibodies may also be useful for in vivo maging of N-cadherin positive tumors and/or for tissue diagnosis and prognosis.
The invention can be practiced alone as single antibodies to treat or prevent tumor growth and metastasis. They may be used as adjuvants or as therapeutics for existing tumors. They may be used in combination to block multiple domains of the N-cadherin protein. They may also be used in combination with chemotherapy or other targeted cancer agents, particularly those that target synergistic signal transduction pathways or those that target downstream or upstream pathways involved in N-cadherin mediated signal transduction.
There are currently no approved therapes or diagnostics targeting N-cadherin. The only drug targeting this pathways has not been highly successful in Phase II trials and has shown no activity in the preclinical models that our invention is active against, suggesting the clear superiority of our approach and our agents.
Accordingly, the invention provides compositions and methods that target N-Cadherin in the diagnosis, prognosis, and treatment of cancers expressing N-Cadherin including, but not limited to, prostate cancer and bladder cancer.